Composition for a topical ophthalmic clear colloidal liquid which undergoes a liquid-gel phase transition in the eye

ABSTRACT

The present invention is directed to a topical ophthalmic composition for a liquid comprised of clear colloidal polar nanolipids delivered in submicron sized particles (Nanopids™), aqueous colloidal lubricants, aqueous polymers, emulsifies, and a unique stabilizing buffer system, which undergoes a liquid-gel phase transition in the eye. Said composition is designed to deliver advanced eye lubricants, protect the three (3) layers of corneal film from dryness, and provide a unique system of Dry Eye treatment that addresses and treats all three layers of corneal tear film. Said composition is further designed to provide a superior delivery system of various Active Pharmaceutical Ingredients (APIs), and/or anti-infective/antibiotic/anti-fungal agents, accepted as safe and efficacious for ophthalmic use.

BACKGROUND OF THE INVENTION

In healthy eyes, blinking induces the formation of tears which form athin film which spreads over the corneal surface of the eye, making thesurface smooth and optically clear, thereby enabling good vision. Saidtear film is formed of three layers: an oil layer (lipids), a water(aqueous) layer, and a layer of mucus. The outermost layer is the lipidlayer; its purpose is to smooth the tear surface and reduce evaporationof the eye's natural lubricants. The middle layer is the water layer;its purpose is to cleanse the eye and wash away any foreign particles orirritants. The innermost layer is the mucus layer; the mucus allows thewater layer to spread evenly over the surface of the eye. Without themucus layer, tears would not adhere to the eye.

Tears are produced by the Lacrimal Glands, located under the eyelids.“Dry Eye” is a condition caused by tear film instability and consequentocular surface degeneration. Dry Eye may occur when the Lacrimal teargland produces insufficient natural tears, in some instances as a normalconsequence of the aging process during which lacrimal tissue maydeteriorate and the lacrimal glands may shrink. Specifically, thelacrimal tissue may deteriorate and the lacrimal glands may shrink.Alternatively, dysfunction of the Meibomain gland may destabilize thetear film, or a blockage may occur in the execratory ducts of thelacrimal gland. Early signs and symptoms of Dry Eye include redness,burning, light sensitivity, gritty sensation, and watery eyes. As thenormal base line tear production decreases, the eyes become dry andirritated. This may result in increased symptoms, including pain,redness blurred vision and infection. Over time, the reduced productionof natural tears leads to dissipation of the lipid and mucous tear filmlayers. This in turn allows for evaporation of the aqueous layer,causing dry spots on the surface of the eye. The resulting impairedcellular surface leads to an unstable tear film, and a pathologicallyshort tear break-up time (TBUT). If untreated, this condition willeventually exacerbate the symptoms noted above and result in ocularsurface damage.

The present invention relates to a composition for a unique cleartopical ophthalmic gel-forming liquid, delivering in a clear colloidalform for the first time submicron sized particles of clear colloidal oildroplets of polar nanolipids (Nanopids™), emulsifiers, and multipleaqueous tearlike ingredients (aqueous lubricants and/or aqueouspolymers). The subject composition is uniquely designed to protect thethree (3) layers of corneal film from dryness, deliver advanced eyelubricants, and to deliver a unique system of Dry Eye treatment thataddresses and treats all three layers of corneal tear film. The sizedistribution of the clear colloidal polar lipids is in the range of 1.0nanometers to 200.0 nanometers, with a preferred upper limit of 50nanometers. The preferred mean average particle size is 13.0 nanometers(standard deviation of 3.2 nanometers) with a population distributionrange of 6.0 nanometers to 22.0 nanometers. The size distribution of theaqueous colloidal particles is in the range of 3.0 nanometers to 200.0nanometers. The preferred mean average particle size is 30.0 nanometers(standard deviation of 15.0 nanometers) with a particle sizedistribution range of 3 nanometers to 150 nanometers.

The subject composition also contains a unique gelling agent (anionicheteropolysachharide) which after introduction into the eye and uponcontact with the cations naturally present in the pre-corneal tear filmforms a clear gel. The composition allows the delivery of colloidalpolar nanolipids in a clear gel form, and the additional benefitsderived therefrom.

The clear (transparent) nature of the composition is a significantadvantage of the invention. Conventional ophthalmic gel preparations,ophthalmic ointments and ophthalmic emulsions are uniformly cloudy oropaque. For example, the compositions of such conventional ophthalmicemulsions consist of large particle sizes that are generally greaterthan 1 micron, and can exceed 24 microns (e.g., Soothe.) When suchconventional preparations are instilled in the eye, the result isprolonged blurred vision. Prolonged blurriness has a negative impact onpatient acceptance of such ophthalmic preparations, and negativelyimpacts on patient compliance with the use of such products as directed.While adjustments in the viscosity of such conventional ophthalmicpreparations may make the resultant formula less viscous, such will notresolve patient complaints of blurriness due to the cloudy/opaque natureof such preparations. In contrast, the clear nature of the subjectcomposition will result in superior acceptance by patients, and asuperior overall patient experience.

The present invention contemplates a unique clear ophthalmic gel-formingliquid designed to remedy the inability of Dry Eye patient's eyes tolubricate themselves through the natural replenishment of the tear film.The clear polar nanolipids play a major role in restoring andmaintaining a healthy outer lipid layer of the tear film. The size,concentration and clarity of the colloidal polar nanolipids areparticularly important for the subject composition. Conventionalophthalmic emulsions containing oil or lipids are cloudy due to theparticle size. The particle size of these emulsions is greater than 1000nanometers (greater than 1 micron). Some of these ophthalmic emulsionscontain non-polar mineral oil with an oil droplet particle size greaterthan 10,000 nanometers (10 microns), in some cases with a particle sizeexceeding 24,000 nanometers (24 microns). Such formulations causeblurring in the eyes of users, negatively impacting on clarity ofvision. Additionally, since they are non-viscous liquid emulsions, alarge percentage of such preparations are blinked away duringadministration into the eye. As a result, only a small fraction of thedose remains in contact with the cornea. Conventional ophthalmic gelpreparations and ophthalmic ointments present similar issues related tocloudiness and loss of the preparations due to their particle size. Bycontrast the subject composition containing the submicron sizednanoparticles, which in addition to allowing for the formation of aclear gel, results in a composition which is more effective inlubricating the eye and maintaining the tear film layers. First, thesubmicron sized particles of colloidal oil droplets of polar nanolipidscomprising the subject composition are not lost as a result of blinking,resulting in prolonged eye exposure to the composition and anypharmaceutically active compounds present. Second, as the compositionremains in colloidal liquid for until instilled into the eye, it iseasier to administer to the eye, as compare to conventional ophthalmicemulsions, gel and/or ointment preparations.

The subject composition's formation of a clear viscous gel onceadministered into the eye further prolongs the delivery of nanolipidsand nano-sized aqueous lubricants into the lacrimal fluid. As a result,the amount delivered is sustained over an extended time, providing acontrolled bioavailability vehicle for delivery of the nanolipids andnano-sized aqueous lubricants to support the tear film. The subjectcolloidal liquid composition also contains a polysaccharide whichundergoes a liquid-gel phase transition under the effect on an increasein cationic strength, and as such is diluted less rapidly which in turnprovides for sustained delivery of the nanoparticles suspended in thesubject composition. The prolonged exposure time provided by the subjectcomposition results in delivery of a more effective concentration of thenanolipids and nano-lubricants to the lacrimal fluid.

The dissipation of the lipid and mucous layers experienced by Dry Eyepatients results in evaporation of the aqueous watery layer, causing dryspots. The resulting impaired ocular surface leads to an unstable tearfilm and a pathologic short tear break-up time (TBUT), which eventuallyresults in ocular surface damage. Normal tear break-up time isapproximately ten (10) seconds. A TBUT shorter than ten (10) secondsindicates a Dry Eye condition. If the tear film breaks up before a blinkoccurs, some portion of the eye will be exposed to desiccating elements.Through prolonged exposure to the air and environmental particulatematter, the unprotected ocular cells become desiccated and die.Eventually, the mucins will not be able to form a smooth ocular surfaceacross the eye. As a result, the ability of the eye's naturally formingtears to adhere to the corneal epithelia is compromised, furthershortening the tear break-up time and intensifying surface exposure.

A clinical study was performed on the composition that is the subject ofthe present invention (see Koch and Karpecki “Altaire Gel FormingSolution Study’ referenced above at the ‘Other Publications’ section.)Clinical observation and testing of the composition as used by Dry Eyepatients demonstrated a considerable improvement in the normal tearbreak-up time. The data showed a significant trend of increased tearbreak-up time, increasing from a 7.68 second TBUT baseline (prior to useof the subject invention) to 11.27 seconds after one (1) month of use ofthe composition. This measurable increase of over 3.5 seconds in TBUT isremarkable from a clinical perspective, since the duration of the studywas only one (1) month and the composition was administered in a minimaldosage (2 times per day). Additionally, the composition significantlyimproved conjunctival staining after one (1) month of use. It alsostatistically improved ‘Dry Eye’ symptoms such as redness, dryness,headaches, feelings of grittiness or sandiness, scratchiness, andblurred vision. After installation of the subject composition suchsymptoms resolved in one (1) hour in eighty percent (80%) of the studysubjects; a full one hundred percent (100%) of study subjects reportedrelief for thirty (30) minutes or more. This is a statisticallysignificant improvement compared to the study baseline. Finally, thereported duration of the relief combined with the quality of visionresults suggest that the subject composition provides a significantduration of relief of symptoms without compromising visual quality andacuity.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a topical ophthalmic compositionfor a liquid comprised of clear colloidal polar nanolipids delivered insubmicron sized particles (Nanopids™), aqueous colloidal lubricants,aqueous polymers, emulsifies, and a unique stabilizing buffer system,which undergoes a liquid-gel phase transition in the eye.

The present invention is also directed to methods of using thesecompositions for delivery of advanced eye lubricants, protecting thethree (3) layers of corneal film from dryness, and a unique system totreat Dry Eye symptoms and conditions of Dry Eye treatment thataddress's and treats all three layers of the corneal tear film.Additionally, the subject composition is applicable as a delivery systemfor various pharmaceutically active compounds (Active PharmaceuticalIngredients) recognized as safe and efficacious for the treatment ofvarious ophthalmic conditions, diseases and/or disorders including butnot limited to Dry Eye, Glaucoma, Ocular hypertension, infection,allergy, irritation, itching, redness and inflammation, and as adelivery system for anti-infectives, antibiotics, and combinationanti-fungals, anti-virus and anti-inflammatory agents.

The composition is comprised of sub-micron sized colloidal polar lipidsformed from one or more non-ionic polyethylene glycol derivatives ofcastor oil and/or hydrogenated castor oil (preferably Polyoxyl 35 CastorOil), an anionic purified polysaccharide (‘Gellan Gum’), one or morebuffering agents (i.e. boric acid, trimethamine), one or more aqueouslubricants, and one or more colloidal aqueous lubricants.

The types of colloidal polar lipids that may be used in the presentinvention are polyethylene glycol derivatives of castor oil andpolyethylene glycol derivatives of hydrogenated castor oil. As usedherein, the term ‘lipids’ primarily refers to Polyoxyl 35 Castor Oilderived from castor oil, and it's equivalent Polyethylene Glycolderivatives of castor oil. The preferred lipid for the present inventionis Polyoxyl 35 Castor Oil NF (a.k.a. Polyoxylethylenglyceroltricinoleat35), trade names PEG 35 Castor Oil (Croda) or cremophor EL (BASF). Whenthe Polyoxyl 35 Castor Oil is hydrated in an aqueous vehicle, colloidalpolar nanolipids composed of sub-micron sized particles of oil dropletsare formed as a clear colloidal liquid. In the present invention, thecolloidal lipids formed from Polyoxyl 35 Castor Oil NF, after hydrationwith aqueous vehicles contain both a hydrophobic function group (i.e.“castor oil”) and a hydrophilic function group (i.e. “PEG”). Thehydrophobic group is non-polar, and having an affinity towards non-polarmolecules, assists in the stabilization of the lipid layer of the tearfilm. Contrastingly, the hydrophilic group is polar, and has an affinitytowards the aqueous layer of the tear film.

A variety of polyethylene glycol derivatives of castor oil and/orhydrogenated castor oil may be used for forming the colloidal particles.The scope of the present invention is not limited to Polyoxyl 35 CastorOil NF/USP. Any and all forms/grades of polyethylene glycol derivativesof castor oils and/or hydrogenated castor oils, including but are notlimited to those specified herein, may be used to form the colloidalparticles. Examples include, but are not limited to, PEG-30 castor oil,PEG-33 castor oil, PEG-36 castor oil, PEG-40 castor oil, PEG-30hydrogenated castor oil and PEG-40 hydrogenated castor oil. There aremany polyethylene glycol derivatives of castor oil [hereinafter PEGcastor oil] and polyethylene glycol derivatives of hydrogenated castoroil [hereinafter PEG Hydrogenated] available commercially that can beused to form the colloidal particles. This exemplification isnon-exclusive.

The clear colloidal polar nanolipid particles are present in a sizerange of 1.0 nanometers to 200.0 nanometers, with a preferred upperlimit of 50 nanometers, with a preferred mean average particle size of13.0 nanometers (standard deviation of 3.2 nanometers) with a populationdistribution range of 6.0 nanometers to 22.0 nanometers. The content ofpolar lipid can be 0.1-15% w/v.

The present invention preferably is a composition comprised of Polyoxyl35 castor oil in an ophthalmic liquid, which can contain a variousamount of nanolipids. The size of such nanolipids particles ispreferably within a narrow size range of 6.0 nanometers to 22.0nanometers. Other sources of oils such as triglycerides andphospholipids can be emulsified to form hydrophobic/hydrophilicproperties, and when hydrated will form colloidal particles. However,the size of such particles is too large and the resulting colloidalliquid is turbid rather than clear. The clarity of the colloidal liquidis dependant on the concentration and size range of the particles. Lipidcolloidal particles that measure less than 50 nanometers will form clearcolloidal liquids, while particles larger than 200 nanometers will formturbid liquids depending on concentration. The larger the particle size,the greater the turbidity.

The content of anionic polysaccharide is 0.05-2 w %, and it has a sizeof 3 to less than 100 nm, preferably 3-60 nm. Preferably, it has a meansize of 7.4-28.6 nm.

Gellan Gum (available for instance under the trade name “GelRite”) isused as a gelling agent in culture medium and also in food products.Aqueous solutions containing about 0.05% to about 2.0% by weight ofGellan Gum are slightly viscous at low ionic strength (and non-viscousin absence of cations) but will undergo a liquid-gel transition when theionic strength is increased. In the composition that is the subject ofthe present invention, such an increase in ionic strength occurs whenthe clear colloidal liquid is introduced into the eye. When ophthalmicliquid containing “Gellan Gum” is instilled into the eye, and uponcontact with the cations present in the pre-corneal tear film, theviscosity of the liquid increases a gel is formed in the eye. After thecomposition undergoes this liquid-to-gel phase transition under theeffect of an increase in cationic strength, said composition is dilutedless rapidly in the eye than conventional ophthalmic solutions, andmakes possible a sustained delivery of the nanoparticles suspended insaid composition. This results in delivery of more effective levels ofconcentration of the nanolipids and nano-aqueous lubricants to thelacrimal fluid.

The composition that is the subject of the present invention may containone or more aqueous polymers that are non-ionic. The polymers providelubrication to the middle layer of the tear film. Said polymers arepresent in the subject composition in a clear colloidal form. The sizeof such colloidal polymers ranges from 3.0 nanometers to 150 nanometers.

The composition is buffered to a pH of 5-7.8, preferably 6.8-7.8. Thebuffering system allows use of the unique gelling agent in a cleartopical ophthalmic liquid that is suitably stable and safe andefficacious for ophthalmic use. Boric Acid and tromethamine arepreferably used in the buffering system of the composition that is thesubject of the present invention. The buffering system used for thecomposition of the gel-forming colloidal liquid was deliberatelyformulated without cationic electrolytes, which is what works to preventformation of a gel prior to the installation of the liquid compositioninto the eye. The buffering system as described herein allows for astable base for the subject ophthalmic liquid composition by controllingthe pH range, maintain the desired osmolality (250 to 400, preferably280 to 330, mOsm/Kg.H₂O), eliminating the use of cations in the base,and preventing precipitation of any of the composition.

As noted above, the subject composition is a clear ophthalmicgel-forming liquid which, after introduction into the eye, forms a cleargel upon contact with the cations naturally present in the pre-cornealtear film. The clear (transparent) nature of the gel is a significantadvantage of the invention. Conventional ophthalmic gel preparations,ophthalmic ointments and ophthalmic emulsions are uniformly cloudy oropaque. When such conventional preparations are instilled in the eye,the result is prolonged blurred vision. Prolonged blurriness negativelyimpacts both on patient acceptance of such ophthalmic preparations, andon patient compliance with the use of such products as directed.Adjustments in the viscosity of such conventional ophthalmicpreparations will not resolve patient complaints of blurriness due tothe cloudy/opaque nature of such preparations.

The present composition is a unique clear ophthalmic gel-forming liquiddesigned to remedy the inability of Dry Eye patient's eyes to lubricateitself through the natural replenishment of the tear film. The clearpolar nanolipids (e.g., that sold under the name Nanopids™) play a majorrole in restoring and maintaining a healthy outer lipid layer of thetear film. The size, concentration and clarity of the colloidal polarnanolipids are particularly important for the subject composition.Conventional ophthalmic emulsions, gel preparations and ointmentscontaining oil or lipids are cloudy due to their larger particle size.These formulations cause blurring in the eyes of users, negativelyimpacting on clarity of vision. Additionally, since they are non-viscousliquid emulsions, a large percentage of such preparations are blinkedaway during administration into the eye. As a result, only a smallfraction of the dose remains in contact with the cornea. By contrast thesubject composition containing the nanoparticles, which in addition toallowing for the formation of a clear gel, are more effective inlubricating the eye and maintaining the tear film layers. The submicronsized particles of colloidal oil droplets of polar nanolipids comprisingthe subject composition are not lost as a result of blinking.

The subject composition's formation of a clear viscous gel onceadministered into the eye results in a prolonged delivery of nanolipidsand nano-sized aqueous lubricants into the lacrimal fluid that issustained over an extended time, providing both a greater degree andlonger duration of support to the tear film. The subject compositionundergoes a liquid-gel phase transition and as such is diluted lessrapidly, which in turn provides for sustained delivery of thenanoparticles suspended in the compositions. The prolonged exposure timeprovided by the subject composition results in delivery of a moreeffective concentration of the nanolipids and nano-lubricants to thelacrimal fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (#081710D): Ophthalmic composition with nanolipids (Nanopids™)containing PEG 35 Castor Oil. FIG. 1 illustrates the formation of thecolloidal liquid. The particles represented are polar nanolipids. Themean diameter of such particles is 11.7 nanometers.

FIG. 2 (#081810A): Ophthalmic composition with nanolipids (Nanopids™),aqueous colloidal lubricants, and aqueous polymers (nano particles) in abuffered liquid. FIG. 2 illustrates the formation of the three peaks ofcolloidal particles that make up the subject composition. The meandiameter of peak 2 is 13.1 nanometers, which consists mostly ofnanolipids. The mean diameter of peak 3 is 122.3 nanometers, whichmainly consists of aqueous nanoparticles from Povidone K-30,Hydroxyethylcellulose, and Polyvinyl Alcohol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to liquid ophthalmic gel-formingcompositions which are comprised of sub-micron sized colloidal polarlipids formed from one or more non-ionic polyethylene glycol derivativesof castor oil and/or hydrogenated castor oil (e.g., Polyoxyl 35 CastorOil), an anionic purified polysaccharide (e.g., ‘Gellan Gum’), one ormore buffering agents (i.e. boric acid, trimethylamine), and preferablyone or more aqueous lubricants, and one or more colloidal aqueouslubricants. The present invention is also directed to methods of usingthese compositions for delivery of advanced eye lubricants, protectionof the three (3) layers of corneal film from dryness, and delivery of aunique system of Dry Eye treatment that addresses and treats all threelayers of corneal tear film, and as a delivery system forpharmaceutically active compounds (a.k.a. Active PharmaceuticalIngredients) to treat various ophthalmic conditions, diseases and/ordisorders including but not limited to Dry Eye, Glaucoma, Ocularhypertension, infection, allergy, irritation, itching, redness andinflammation.

The types of colloidal polar lipids that may be used in the presentinvention are polyethylene glycol derivatives of castor oil andpolyethylene glycol derivatives of hydrogenated castor oil. PEG castoroil and PEG hydrogenated castor oil are predominantly glyceryltricinoleyl polyethylene glycols and tri-12-hydroxylstearyl polyethyleneglycols, respectively. As used herein, the term ‘lipids’ primarilyrefers to Polyoxyl 35 Castor Oil derived from castor oil, and it'sequivalent Polyethylene Glycol derivatives of castor oil. Castor oil isobtained by the pressing of seeds of the ricinus communis plant followedby heat clarification of the oil.

Many sources of lipids can be used in the present invention, such astriglycerides or soybean phospholipid (a.k.a. “soy lecithin.”) Thepreferred lipid for the present invention is Polyoxyl 35 Castor Oil NF(a.k.a. Polyoxylethylenglyceroltricinoleat 35), also identified by thetrade names PEG 35 Castor Oil (manufactured by Croda) or cremophor EL(manufactured by BASF). Polyoxyl 35 Castor Oil NF contains mainly thetri-ricinoleate ester of ethoxylated glycerol, with small amounts ofpolyethylene glycol ricinoleate and the corresponding free glycols. Itresults from the reaction of glycerol ricinoleate with about thirty-five(35) moles of ethylene oxide. The hydrophobic part of Polyoxyl 35 CastorOil are glycerol-polyethylene glycol ricinoleate together with fattyacid esters of polyethylene glycol and some uncharged castor oil. Thesmaller hydrophilic part of Polyoxyl 35 Castor Oil are polyethyleneglycols and ethoxylated glycols. The hydrophobic part is about 83% whilethe hydrophilic part is about 17%. Polyoxyl 35 castor oil is a non-ionicsurfactant, the functional group causes ricinoleic acid (and castor oil)to be unusually polar and allows chemical derivatization that is notpractical in most other seed oils. In the present invention, thecolloidal lipids formed from Polyoxyl 35 Castor Oil NF, after hydrationwith aqueous vehicles contain both a hydrophobic function group (i.e.“castor oil”) and a hydrophilic function group (i.e. “PEG”). Thehydrophobic group is non-polar, and having an affinity towards non-polarmolecules, assists in the stabilization of the lipid layer of the tearfilm. Contrastingly, the hydrophilic group is polar, and has an affinitytowards the aqueous layer of the tear film.

A variety of polyethylene glycol derivatives of (hydrogenated) castoroil may be used for forming the colloidal particles. The scope of thepresent invention is not limited Polyoxyl 35 Castor Oil NF/USP. Any andall forms/grades of polyethylene glycol derivatives of castor oilsand/or hydrogenated castor oils, including but are not limited to thosespecified herein, may be used to form the colloidal particles. Examplesinclude, but are not limited to, PEG-30 castor oil, PEG-33 castor oil,PEG-36 castor oil, PEG-40 castor oil, PEG-30 hydrogenated castor oil andPEG-40 hydrogenated castor oil. There are many polyethylene glycolderivatives of castor oil [hereinafter PEG castor oil] and polyethyleneglycol derivatives of hydrogenated castor oil [hereinafter PEGHydrogenated] available commercially that can be used to form thecolloidal particles.

The clear colloidal polar nanolipid particles are present in a sizerange of 1.0 nanometers to 200.0 nanometers, with a preferred upperlimit of 50 nanometers, with a preferred mean average particle size of13.0 nanometers (standard deviation of 3.2 nanometers) with a populationdistribution range of 6.0 nanometers to 22.0 nanometers.

When the Polyoxyl 35 Castor Oil is hydrated in an aqueous vehicle,colloidal polar nanolipids composed of sub-micron sized particles of oildroplets are formed as a clear colloidal liquid. The size of suchnanolipids particles is preferably within a narrow size range of 6.0nanometers to 22.0 nanometers. The present invention is a compositioncomprised of Polyoxyl 35 castor oil in an ophthalmic liquid, which cancontain various amounts of nanoliquids. The amount of Polyoxyl 35 castoroil (polar lipid) can be 0.1% to 15% weight-by-volume.

Other sources of oils such as triglycerides and phospholipids can beemulsified to form hydrophobic/hydrophilic properties, and when hydratedwill form colloidal particles. However, the size of such particles istoo large and the resulting colloidal liquid is turbid rather thanclear. The clarity of the colloidal liquid is dependant on theconcentration and size range of the particles. Lipid colloidal particlesthat measure less than 50 nanometers will form clear colloidal liquids,while particles larger than 200 nanometers will form turbid liquidsdepending on concentration. The larger the particle size, the greaterthe turbidity.

Colloidal polar lipids can be formed by emulsification of soy lecithin“phospholids” with Polysorbate 80. After hydration in an aqueousvehicle, the amount that can be emulsified and still result in a clearcolloidal liquid is small. When 0.05% of soy lecithin is emulsified with4% Polysorbate 80 and then hydrated to 100 mL of Purified Water, a clearcolloidal liquid of nanolipids is formed. However, when 0.05% of soylecithin is emulsified with 3% or less of Polysorbate 80 and thenhydrated to 100 mL of Purified Water, a turbid colloidal liquid isformed. Turbid colloidal liquids are not suitable for an ophthalmiccomposition.

Triglycerides (e.g., those sold under the trade names “Neobee M-5” and“Neobee 1053”, manufactured by Stepen) when emulsified with Polysorbate80 and then hydrated in a hydrophilic vehicle form an opaque/turbid andunstable emulsion. The size of the particle is too large. Theseemulsions are not suitable for an ophthalmic composition. However, whena small amount of triglycerides (0.1%) is emulsified in a Polyoxyl 35Castor Oil and then hydrated in a hydrophilic vehicle, a clear colloidalnanolipid liquid composition is formed. The clear colloidal liquidcomposition contains both Castor Oil and triglcerides nanolipids.

Gellan Gum (trade name “GelRite”, manufactured by Kelco and Co.) is useda gelling agent in culture medium and also in food products. Thestructure of this heteropolysaccharide consists of the followingrepeating unit→3)-β-D-Glcp-(→4)-β-D-GlcpA-(1→4)-β-D-Glcp(1→4)-a-L-Rhap(1→which may, or may not, be partially O-acetylated. Said structure isdescribed as above in U.S. Pat. No. 4,326,053 (patent holder Merck andCo., Inc. Rahway, N.J.); said structure is also described in particularby Jansson and Linberg, Carbohydr. ROS. 124 35-9 (1983).

Aqueous solutions containing about 0.05% to about 2.0% by weight ofGellan Gum are slightly viscous at low ionic strength (and non-viscousin absence of cations) but undergo a liquid-gel transition when theionic strength is increased. In the composition that is the subject ofthe present invention, such an increase in ionic strength occurs whenthe clear colloidal liquid is introduced into the eye. The rigidity ofthe gel can be modified by adjusting the polymer concentration.Additionally, when introduced into an aqueous solution Gellan Gum isboth thixotropic and thermoplastic. These two properties enable itsfluidity to be increased by shaking or slightly warming the samplebefore administration to the eye.

When ophthalmic liquid containing a purified non-ionicheteroploysacccharide “Gellan Gum” is instilled into the eye, and uponcontact with the cations present in the pre-corneal tear film, theviscosity of the liquid increases and a gel is formed in the eye.Liquids containing 0.05% to approximately 2.0% by weight of “Gellan Gum”are non-viscous; where by design the liquid contains no cations, saidliquid will undergo a liquid-to-gel transformation when the ionicstrength (cations) is increased. In the instance of the compositionwhich is the subject of the present invention, such an increase in theionic strength of the ophthalmic aqueous liquid will occur when it isintroduced into the eye, resulting in the forming of gel drops in theeye. After the colloidal liquid containing a polysaccharide undergoesliquid-to-gel phase transition under the effect of an increase incationic strength, said composition is diluted less rapidly in the eyethan conventional ophthalmic solutions, and makes possible a sustaineddelivery of the nanoparticles suspended in said composition. Thisprocess residence time permitted by the composition that is the subjectof the present invention results in delivery of more effective levels ofconcentration of the nanolipids and nano-aqueous lubricants to thelacrimal fluid.

Boric Acid and tromethamine are used in the buffering system of thecomposition that is the subject of the present invention. The bufferingsystem used for the composition of the gel-forming colloidal liquid wasdeliberately formulated without cationic electrolytes. The lack ofcations in the product composition is what works to prevent formation ofa gel prior to the installation of the liquid composition into the eye.The composition is buffered to a pH range of 5.0 to 7.8. The preferredpH range is 6.8 to 7.8. The concentration of boric acid ranges fromapproximately 0.1% to 10.0%. The concentration of trimethamine rangesfrom approximately 0.1% to 5.0%. The buffering system as describedherein allows for a stable base for the subject ophthalmic liquidcomposition by controlling the pH range, maintaining the desiredosmolality, eliminating the use of cations in the base, and preventingprecipitation of any of the composition.

The composition that is the subject of the present invention may containone or more aqueous polymers that are non-ionic, such as PolyvinylAlcohol, Hydroxyethylcellulose and Povidone K-30 as well as propyleneglycol, polyethylene glycol, sodium carboxymethylcellulose, and manyothers. The polymers provide lubrication to the middle layer of the tearfilm. Said polymers are present in the subject composition in a clearcolloidal form. The size of such colloidal polymers range from 3.0nanometers to 150 nanometers. The concentration of polyvinyl alcohol incomposition that is the subject of the present invention ranges from0.1% to 5.0%. The concentration of Hydroxyethylcellulose ranges from0.1% to 1.0% and the concentration of Povidone K-30 ranges from 0.1% to5.0%. Other non-ionic lubricants such as polysorbate 80, propyleneglycol and glycerine also incorporated into the subject composition toprovide lubrication to the middle aqueous layer of tear film. Theconcentration of polysorbate 80 ranges from 0.1% to 5.0%; theconcentration of propylene glycol ranges from 0.1% to 2.0%, and theamount of Povidone K-30 ranges from 0.1% to 5.0%.

The application of the composition that is the subject of the presentinvention to a formulation also including various pharmaceutical activecompounds is illustrated by the examples below. These include

-   -   (A) Redness Relief: tetrahydrozoline HCl or naphazoline HCl, in        a dose recognized as safe and efficacious for topical ophthalmic        use, can be incorporated into the composition that is the        subject of the present invention to provide redness relief.    -   (B) Allergy Relief: Addition of either ketotafen fumarate,        olopatadine HCl, azelastine HCl, epinastine HCl, naphazoline HCl        and pheniramine maleate, or lotpredenol etabonate to the        composition that is the subject of the present invention will        provide relief of better and a longer duration of relief allergy        eye symptoms, including but not limited to the relief and        prevention of itching associated with allergic conjunctivitis.    -   (C) Delivery Of Anti-Infectives, Antibiotics, And Combination        Anti-Fungals, Anti-Virus And Anti-Inflammatory Agents: The        following agents, in a dose recognized as safe and efficacious        for topical ophthalmic use, could be incorporated into the        composition that is the subject of the present invention:        ciproflaxin HCl, gatifloxacin, gentamicin sulfate, gramicidin,        erythromycin, levoflaxin, moxifloxacin HCl, natamycin, neomycin        sulfate, ofloxacin, polymixin B sulfate, sodium sulfacetamide,        tobramycin, trimethoprim sulfate, bacitracin, dexamethasone,        flurometholone, hydrocortisone, prednisolone, tripfluridine,        naproxen, diclofenac, surofen, keterolac, and tetrahydocortisol.    -   (D) Treatment Of Various Ophthalmic Conditions, Diseases And/Or        Disorders Including But Not Limited To Dry Eye, Glaucoma, Ocular        Hypertension, Infection, Allergy, Irritation, Itching, Redness        And Inflammation: Dry Eye (including but not limited to        cyclosporine and derivatives thereof), anti-hypertensive agents        (para-aminoclonidine), anti-glaucoma agents (including but not        limited to betaxolol, timolol maleate, pilocarpine HCl, carbonic        anhydrase inhibitors, prostglandins), neuro-protective agents,        dopaminergic antagonists, muco-secretagogue agents, angiostatic        agents, proteins, growth factors (i.e. epidermal growth factor)        and pain relievers, may be efficaciously treated by        incorporation into the subject composition the pharmaceutically        active ingredients/agents listed herein in dosages recognized as        safe and efficacious.    -   (E) Delivery of Vitamin and/or Homeopathic Agents: the subject        composition is also applicable to the delivery of vitamins        and/or homeopathic preparations in a gel drop) into the eye for        treatment of various ophthalmic conditions, diseases and/or        disorders including but not limited to dry eye, glaucoma, ocular        hypertension, infection, allergy, irritation, itching, redness        and inflammation.

In summary, the composition is a uniquely designed composition of anophthalmic liquid containing a clear gelling agent designed to deliveradvanced eye lubricants, protect the three (3) layers of corneal filmfrom dryness, and delivery of a unique system of dry eye treatment thataddresses and treats all three layers of corneal tear film. The gellingagent is an anionic heteropolysaccharide. The ophthalmic compositioncontains clear colloidal polar nanolipids, and a stabilizing buffersystem, and may also contain aqueous lubricants and/or aqueous polymersand emulsifiers, aqueous colloidal lubricants and an efficaciouspreservative system. The unique combination of the elements of thecomposition with the gelling agent in the stable buffering systemresults in a unique clear gel-forming ophthalmic liquid which deliversadvanced eye lubricants, protects the three (3) layers of corneal filmfrom dryness, and delivers multiple stages of dry eye treatmentimpacting on all three (3) layers of corneal tear film. Additionally, asnoted above, the subject composition is also suitable for theefficacious delivery of various pharmaceutically active ingredients forthe treatment of various of ophthalmic conditions.

EXAMPLE I

Topical ophthalmic composition containing nanolipids and otherlubricants.

-   -   Phase I: compound amount (w/v) Gelrite ‘Gellan Gum’ 0.1%,        polyvinyl alcohol 0.5%, hydroxyethylcellulose 0.3%, povidone        K-30 2.0%, PEG 35 Castor Oil 1.0% and purified water q.s. to        80%. While mixing add the above items while maintaining a        temperature of 85° C.±5° C. until completely dissolved. Transfer        to a pressure tank and autoclave at 121.1° C. for 45 minutes,        the cool down to 25° C.    -   Phase II: compound amount (w/v) of Boric Acid 1.12%,        tromethamine 0.65%, Glycerine 0.5%, propylene glycol 0.3%,        polysorbate 80 1.0%, sorbic acid 0.1% and purified water q.s. to        20%. Mix until dissolved. Aseptically filter the solution        through a 0.2 micron filter into the sterile pressure tank        containing phase I. Mix the entire batch for 30 minutes while        maintaining the temperature at 25° C.

EXAMPLE II

Topical ophthalmic composition containing Naphazoline HCl

-   -   Phase I: compound amount (w/v) Gelrite ‘Gellan Gum’ 0.1%,        polyvinyl alcohol 0.5%, hydroxyethylcellulose 0.3%, povidone        K-30 2.0%, PEG 35 Castor Oil 1.0% and purified water q.s. to        80%. While mixing add the above items while maintaining a        temperature of 85° C.±5° C. until completely dissolved. Transfer        to a pressure tank and autoclave at 121.1° C. for 45 minutes,        the cool down to 25° C.    -   Phase II: compound amount (w/v) of compound amount (w/v) of        Boric Acid 1.12%, tromethamine 0.65%, Glycerine 0.5%, propylene        glycol 0.3%, polysorbate 80 1.0%, Naphazoline HCl 0.03%, sorbic        acid 0.1% and purified water q.s. to 20%. Mix until dissolved.        Aseptically filter the solution through a 0.2 micron filter into        the sterile pressure tank containing phase I. Mix the entire        batch for 30 minutes while maintaining the temperature at 25° C.

EXAMPLE III

Topical ophthalmic composition containing Tetrahydrozoline HCl

-   -   Phase I: compound amount (w/v) Gelrite ‘Gellan Gum’ 0.1%,        polyvinyl alcohol 0.5%, hydroxyethylcellulose 0.3%, povidone        K-30 2.0%, PEG 35 Castor Oil 1.0% and purified water q.s. to        80%. While mixing add the above items while maintaining a        temperature of 85° C.±5° C. until completely dissolved. Transfer        to a pressure tank and autoclave at 121.1° C. for 45 minutes,        the cool down to 25° C.    -   Phase II: compound amount (w/v) of compound amount (w/v) of        Boric Acid 1.12%, tromethamine 0.65%, Glycerine 0.5%, propylene        glycol 0.3%, polysorbate 80 1.0%, Tetrahydrozoline HCl 0.05%,        sorbic acid 0.1% and purified water q.s. to 20%. Mix until        dissolved. Aseptically filter the solution through a 0.2 micron        filter into the sterile pressure tank containing phase I. Mix        the entire batch for 30 minutes while maintaining the        temperature at 25° C.

What is claimed is:
 1. An ophthalmic liquid adapted for the treatment ofdry eye consisting essentially of water, colloidal oil dropletscontaining clear nano-size polar lipid which is nonionicpolyoxyethylated castor oil or nonionic polyoxyethylated hydrogenatedcastor oil having a particle size of 1-50 nm, and gellan, which isbuffered to a pH of 5-7.8, is free of cationic electrolytes, and has anosmolality of 250-400 mOsm/kg.H₂O, said liquid being a clear liquidwhich forms a clear gel upon topical contact with the eye, and whereinsaid liquid is free of pharmaceutically acceptable active agent.
 2. Theophthalmic liquid of claim 1 in which the composition is buffered to apH of 6.8-7.8.
 3. The ophthalmic liquid of claim 2 in which the polarlipid has a mean size of 9.8-16.2 nm, and the content of polar lipid is0.1-15% w/v.